Chronic alcohol abuse is the most important "life style" risk factor for osteoporosis. The long-term goal of the proposed research is to understand the cellular and molecular mechanisms responsible for mediating alcohol's detrimental actions on the skeleton and, with this improved understanding, to develop effective countermeasures. Research performed during the current funding interval provides strong evidence that alcohol-induced bone loss is due to a disturbance in the bone remodeling cycle. Specifically, an imbalance in the coupling of bone formation to the prevailing rate of bone resorption creates inadequate new bone to compensate for bone resorption, resulting in net bone loss. At the molecular level, we have established a clear positive association between bone formation and insulin-like growth factor-I (IGF-1) gene expression in bone tissue. Furthermore, the architectural, cellular and gene expression changes in tibiae of rats fed alcohol are strikingly similar to those that follow hypophysectomy (HYPOX), suggesting that the underlying mechanisms for the skeletal response to alcohol abuse and growth hormone (GH) deficiency are similar. Because most of the effects of GH on bone cells are mediated by locally produced IGF-1, the detrimental skeletal effects of alcohol abuse and GH deficiency may share disturbed IGF-1 signaling as a common pathway. The antagonistic effects of HYPOX on bone formation can be reversed with parathyroid hormone (PTH), which up-regulates IGF-1 expression by bone cells. Based on these findings, our working hypotheses are that alcohol-induced osteoporosis is largely due to decreased IGF-1 expression by osteoblasts, and can be prevented or reversed by treatment with PTH. We propose to test these hypotheses in adult and adolescent female rat models for chronic alcohol abuse by determining changes in bone and mineral metabolism in: (1) HYPOX and intact rats fed alcohol; (2) HYPOX and intact rats fed alcohol and treated with GH; (3) HYPOX and intact rats fed alcohol and treated with IGF-1; and (4) HYPOX and intact rats simultaneously fed alcohol and treated with PTH; and (5) intact rats fed alcohol to induce bone loss and then treated with PTH. A suite of complementary techniques will be employed in these experiments to evaluate the skeletal changes, including dynamic and static bone histomorphometry, bone densitometry, micro-CT, biochemical markers, mechanical testing, immunohistochemistry, radioautography and RNA analysis by Northern blots and RNase protection assays.